Cardiovascular disease is a leading cause of mortality. Although many therapies attempt to improve functionality of the heart, for chronic heart failure, cardiac transplantation is typically the only long term option. Owing to low availability of donor hearts, improved treatments are needed. Administering bone-marrow-derived mesenchymal stem cells (MSCs) has beneficial effects for a patient that have experienced a myocardial infarction (MI), and human clinical trials demonstrated modest, yet significant, improvements in cardiac performance. However, cell therapy for heart failure is limited by the lack of implanted cell retention in the infarcted heart. Thus, there is a need for improvement.
Kisiday et al. report a self-assembling peptide hydrogel fosters chondrocyte extracellular matrix production and cell division. PNAS, 2002, 99(15):9996-10001. Davis et al. report local myocardial insulin-like growth factor 1 (IGF-1) delivery with biotinylated peptide nanofibers improves cell therapy for myocardial infarction. PNAS, 2006, 103, 8155-8160. Padin-Iruegas et al. report cardiac progenitor cells and biotinylated insulin-like growth factor-1 nanofibers improve endogenous and exogenous myocardial regeneration after infarction. Circulation, 2009, 120, 876-887. Kyle et al., report the production of self-assembling biomaterials for tissue engineering. Trends Biotechnol, 2009, 27(7):423-33. See also Segers & Lee, Drug Discovery Today, 2007, 12, 561-568, U.S. Pat. Nos. 7,399,831, and 8,299,032, and US Published Application Numbers 2013/0053324 and 2012/0010140.
Notch signaling is an evolutionarily conserved intercellular communication pathway that regulates diverse cellular processes, ranging from cell-fate decision, differentiation, and proliferation to apoptosis. See Kopan et al., Cell, 2009, 137: 216-33. Activation of the Notch receptor by adjacent cell surface-bound ligands of the Jagged and Delta family leads to proteolytic cleavage and nuclear translocation of the Notch intracellular domain (NICD). Apart from regulating normal development and damage-induced repair, Notch signaling has also been found to promote cardiomyocyte survival. Notch activation promotes cardiac gene expression in circulating endothelial progenitor cells, bone-marrow derived MSCs, and cardiac progenitors. See Niessen & Karsan, Circ Res, 2008, 4:1169-1181; Raya et al., PNAS, 2003, 4:11889-11895; Beltrami et al., Cell, 2003, 4:763-776; and Boni et al., PNAS, 2008, 4:15529-15534. Nickoloff et al., report Jagged-1 mediated activation of Notch signaling induces complete maturation of human keratinocytes through NF-kappaB and PPARgamma. Cell Death Differ, 2002, 9(8):842-55.
Boopathy et al. report the modulation of cardiac progenitor cell function by hydrogel-dependent Notch1 activation. Biomaterials, 2014, 35(28):8103-12. Boopathy & Davis report self-assembling peptide-based delivery of therapeutics for myocardial infarction. Methods Mol Biol, 2014, 1141:159-64. Levit et al. report cellular encapsulation enhances cardiac repair. J Am Heart Assoc, 2013, 2(5):e000367.
References cited herein are not an admission of prior art.